Safety and Efficacy of Nilotinib vs. Imatinib in the Treatment of Newly Diagnosed Chinese Ph+ CML-CP Patients

ENESTChina: A Phase III Multi-center, Open-label, Randomized Study of Nilotinib Versus Imatinib in Chinese Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

The study will compare the efficacy and safety of Nilotinib versus Imatinib in newly diagnosed Chinese patients with CML-CP.

Inclusion Criteria:

• Patients of Chinese ethnicity greater than or equal to 18 years of age

• ECOG 0, 1, or 2.

• Patients with CML-CP (Ph+) within 6 months of diagnosis (date of initial diagnosis is the date of first cytogenetic analysis). Standard conventional cytogenetic analysis must be done on bone marrow. (FISH cannot be used)

• Diagnosis of chronic myelogenous leukemia in chronic phase with cytogenetic confirmation for the presence of Philadelphia chromosome of (9;22 translocation; less than 20 metaphases may be used for diagnosis

• Documented chronic phase CML will meet all the criteria defined by:

  • < 15% blasts in peripheral blood and bone marrow
  • < 30% blasts plus promyelocytes in peripheral blood and bone marrow
  • < 20% basophils in the peripheral blood
  • ≥ 100 x 109/L (≥ 100,000/mm3) platelets

• No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly

• Adequate organ function as defined by:

  • Total bilirubin < 1.5 x ULN
  • SGOT and SGPT < 2.5 x ULN
  • Creatinine < 1.5 x ULN
  • Serum amylase and lipase ≤ 1.5 x ULN
  • Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related.

• Patients must have the following laboratory values (≥ LLN (lower limit of normal) or corrected to within normal limits with supplements prior to the first dose of study medication.):

  • Potassium ≥ LLN
  • Magnesium ≥ LLN
  • Phosphate ≥ LLN
  • Total calcium (corrected for serum albumin) ≥ LLN.

• Ability to provide written informed consent prior to any study related screening procedures being performed.

Exclusion Criteria:

• Patients with previously documented T315I mutations;
• Treatment with tyrosine kinase inhibitor(s) prior to study entry is not allowed, except in the following situation: in emergent cases where the patient requires disease management while awaiting study start, commercial supplies of Gleevec/Glivec at any dose may be prescribed to the patient but for no longer than 2 weeks in duration.
• Treatment with IFN for more than 3 months.
• Impaired cardiac function including any one of the following:
• Complete left bundle branch block
• Long QT syndrome or a known family history of long QT syndrome.
• History of or presence of clinically significant ventricular or atrial tachyarrhythmias
• Clinically significant resting bradycardia (<50 beats per minute)
• QTc > 450 msec If QTcF >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc
• History of clinically documented myocardial infarction within past 12 months
• History of unstable angina (during the last 12 months)
• Other clinically significant heart disease (e.g., congestive heart failure or uncontrolled hypertension).
• Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required).
• Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection).
• History of significant congenital or acquired bleeding disorder unrelated to cancer.
• Major surgery within 4 weeks prior to Day 1 of study or who have not recovered from prior surgery.
• Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 30 days of Day 1.
• History of non-compliance to medical regimens or inability to grant consent.
• Patients with another primary malignancy except if the other primary malignancy is neither currently clinically significant or requiring active intervention
• Patients actively receiving therapy with strong CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. See link for complete list of these medications: http://medicine.iupui.edu/flockhart/table.htm or reference Protocol post text appendix 1.
• Patients actively receiving therapy with strong CYP3A4 inducers (e.g., dexamthasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbitol, St. John's Wort) and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. See link for complete list of these medications: http://medicine.iupui.edu/flockhart/table.htm or reference Protocol post text appendix 1.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery)
• History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis.
• Acute or chronic liver, pancreatic or severe renal disease considered unrelated to disease.
• Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug (Please see http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm for a comprehensive list of agents that prolong the QT interval).
• Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior to baseline and (d) female of childbearing potential unwilling to use contraceptive precautions throughout the trial (post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential)

Other protocol-defined inclusion/exclusion criteria may apply